Infortispir Respimat (Solution) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

Boehringer Ingelheim Pharma, GmbH & Co. KG (Germany)

ATC Code

R03AC19 (Olodaterol)

Active Substance

Olodaterol (Rec.INN registered by WHO)

Dosage Form

Infortispir Respimat

Inhalation solution 2.5 mcg/dose: 4.5 ml cartridges

Dosage Form, Packaging, and Composition

4.5 ml – cartridges (1) – cylinders (1) complete with an inhaler – cardboard packs.

Clinical-Pharmacological Group

Bronchodilator drug – beta₂-adrenergic agonist

Pharmacotherapeutic Group

Selective beta2-adrenomimetic

Pharmacological Action

Bronchodilator agent, beta₂-adrenomimetic. Olodaterol has high affinity and selectivity for β₂-adrenergic receptors. Activation of β₂-adrenergic receptors in the airways leads to stimulation of intracellular adenylate cyclase, which is involved in the synthesis of cyclic 3,5-adenosine monophosphate (cAMP). Increased cAMP levels cause bronchodilation by relaxing smooth muscle cells in the airways. Olodaterol is a long-acting selective β₂-adrenergic receptor agonist, characterized by a rapid onset of action and a long duration of effect of at least 24 hours.

β₂-adrenergic receptors are present not only in airway smooth muscle but also on the surface of many other cells, including in the epithelium and endothelium of the lungs and heart. The exact function of β₂-receptors in the heart is not known, but their presence indicates the possibility of an effect on the heart even with highly selective beta₂-adrenergic agonists. It has been established that a single administration of olodaterol in doses of 10, 20, 30, and 50 mcg led to an increase (compared to placebo) in the QT interval (compared to baseline) within 20 min-2 hours, which on average increased from 1.6 ms (Olodaterol 10 mcg dose) to 6.5 ms (Olodaterol 50 mcg dose) with increasing dose. No trends were found for changes in mean heart rate or frequency and type of extrasystoles depending on dose or time.

Olodaterol at a dose of 5 mcg once daily (in the morning) leads to a significant improvement (p<0.0001) in lung function within 5 minutes after the first dose (mean increase in FEV₁ was 0.130 L compared to a pre-treatment baseline of 1.18 L). Significant improvement in lung function was maintained for 24 hours; the mean increase in FEV₁ AUC_0-3 was 0.162 L compared to placebo, p<0.0001; the mean increase in trough (24-hour) FEV₁ was 0.071 L compared to placebo, p<0.0001.

In two exercise tolerance studies, Olodaterol was found to increase the time to fatigue compared to placebo (by 14% p=0.0002 and by 11.8% p=0.0018, respectively). Olodaterol also reduces functional residual capacity compared to placebo, leading to an increase in inspiratory capacity at rest and during exercise.

Pharmacokinetics

Olodaterol is characterized by linear pharmacokinetics.

After a single inhalation administration in doses from 5 to 70 mcg, as well as after multiple administrations in doses from 2 to 20 mcg once daily, bioavailability increased proportionally with increasing dose.

After repeated once-daily administration, steady state was reached after 8 days, and bioavailability increased by 1.8-fold compared to single-dose administration.

Olodaterol is rapidly absorbed after inhalation administration. C_max in plasma is usually reached within 10-20 minutes. In healthy volunteers after inhalation, the absolute bioavailability of olodaterol was about 30%, and after oral administration it was about 1%. Thus, the systemic exposure of olodaterol after inhalation administration is mainly due to absorption in the lungs, and the contribution of the swallowed portion of the dose to systemic exposure is negligible.

Olodaterol after inhalation administration and intravenous administration is characterized by multicompartmental distribution kinetics. V_d is 1110 L, indicating extensive distribution of the drug in tissues. The binding of olodaterol to human plasma proteins in vitro is concentration-independent and is approximately 60%.

Olodaterol is extensively metabolized by direct glucuronidation and O-demethylation of the methoxylated part of the molecule followed by conjugation. Of the six identified metabolites, only one unconjugated demethylated derivative (SOM 1522) binds to β₂-receptors; however, this metabolite was not detected in plasma after long-term inhalation administration of olodaterol at the recommended therapeutic dose or at doses 4 times the therapeutic dose. Therefore, it is believed that the pharmacological action is due solely to olodaterol itself.

The O-demethylation of olodaterol involves the isoenzymes CYP2C9 and CYP2C8, and (to a minor extent) CYP3A4. The formation of olodaterol glucuronides involves the uridine diphosphate glucose-glucuronosyltransferase isoforms, UGT2B7, UGT1A1, 1A7 and 1A9.

The total clearance of olodaterol in healthy volunteers is 872 ml/min, and renal clearance is 173 ml/min. The terminal T_1/2 after intravenous administration of the drug is 22 hours, while the terminal T_1/2 after inhalation administration is approximately 45 hours. It follows that in the latter case, elimination is more dependent on absorption.

The total isotopically labeled dose excreted by the kidneys (including the parent compound and all metabolites) was 38% after intravenous administration and 9% after oral administration. The total isotopically labeled dose of unchanged olodaterol excreted by the kidneys was 19% after intravenous administration. The total isotopically labeled dose excreted via the intestine was 53% after intravenous administration and 84% after oral administration.

More than 90% of the dose was excreted after intravenous administration within 5 days and after oral administration within 6 days. After inhalation administration, the excretion of unchanged olodaterol in urine over the dosing interval was 5-7% of the dose in healthy volunteers at steady state.

Indications

For long-term maintenance therapy in patients with COPD, including chronic bronchitis and emphysema, to reduce airway obstruction, improve quality of life and exercise tolerance.

ICD codes

Dosage Regimen

For inhalation use only.

Administer the recommended therapeutic dose of 5 mcg once daily.

Use one inhalation per day at the same time each day.

Do not exceed the prescribed dose.

If a dose is missed, take it as soon as remembered on the same day.

Do not use a double dose to make up for a forgotten one.

This medication is for long-term maintenance therapy of COPD and is not indicated for the relief of acute bronchospasm.

Always have a rescue inhaler available for immediate symptom relief.

If the prescribed dosage does not provide adequate control of symptoms, or if the need for a rescue inhaler increases, consult a physician immediately.

Before first use, prime the inhaler by releasing test sprays towards the ground until a cloud is visible, then repeat three more times.

If not used for more than 3 days, prime the inhaler again by releasing one test spray.

If not used for more than 21 days, re-prime by releasing test sprays until a cloud is visible, then repeat three more times.

Clean the mouthpiece, including the metal part inside, with a damp cloth once weekly.

The cartridge is finished when the dose indicator enters the red area of the scale and locks.

Do not discontinue therapy without medical consultation.

Adverse Reactions

From the respiratory system nasopharyngitis.

From the nervous system dizziness.

From the cardiovascular system arterial hypertension.

From the skin rash.

From the musculoskeletal system: arthralgia.

The possibility of developing side effects characteristic of the entire class of β-adrenergic agonists should be considered: tachycardia, arrhythmia, palpitations, myocardial ischemia, angina pectoris, arterial hypertension or hypotension, tremor, headache, nervousness, insomnia, dizziness, dry mouth, nausea, muscle spasm, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis.

Contraindications

Childhood and adolescence under 18 years of age, hypersensitivity to olodaterol.

Use in Pregnancy and Lactation

Use during pregnancy and lactation (breastfeeding) is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.

There are no clinical data on the effect of olodaterol on the course of pregnancy. In preclinical studies, when olodaterol was administered in high doses, several times higher than therapeutic doses, effects typical of β₂-adrenergic agonists were observed.

The inhibitory effect of olodaterol on uterine contractility should be taken into account.

There are no clinical data on the use of olodaterol during lactation.

Special Precautions

Use with caution in cardiovascular diseases, including unstable coronary artery disease, cardiac arrhythmias, QT interval prolongation, hypertrophic obstructive cardiomyopathy, arterial hypertension, thyrotoxicosis, seizures, as well as in patients with a history of diseases such as myocardial infarction or hospitalization for heart failure (within the previous year), life-threatening arrhythmia, paroxysmal tachycardia with heart rate >100 beats/min.

Olodaterol is not intended for the treatment of acute episodes of bronchospasm, i.e., as a rescue medication.

Olodaterol is intended for maintenance treatment of patients with COPD. Since in the general COPD population, patients over 40 years of age significantly predominate, when prescribing the drug to patients under 40 years of age, spirometric confirmation of the COPD diagnosis is required.

Olodaterol should not be used for bronchial asthma. The long-term efficacy and safety of olodaterol in bronchial asthma have not been studied.

Long-acting β₂-adrenergic agonists should be used with caution in patients with unusual reactions to sympathomimetic amines.

β₂-adrenergic agonists may cause significant hypokalemia in some patients, creating preconditions for the occurrence of adverse cardiovascular reactions. The decrease in serum potassium is usually transient and does not require replacement. In patients with severe COPD, hypokalemia may progress due to hypoxia and concomitant therapy and increase the risk of arrhythmias.

Inhalation use of β₂-adrenergic agonists in high doses may lead to an increase in plasma glucose levels.

Olodaterol should not be used in combination with any other medicinal product containing long-acting β₂-adrenergic agonists.

Effect on ability to drive vehicles and operate machinery

Studies on the effect of olodaterol on the ability to drive vehicles and operate machinery have not been conducted. During treatment, patients should exercise caution when performing these activities, as dizziness may develop.

Drug Interactions

When used concomitantly with other adrenergic drugs, an increase in the side effects of olodaterol is possible.

Concomitant use of xanthine derivatives, steroids, or diuretics (not belonging to the potassium-sparing group) may enhance the hypokalemic effect of β-adrenergic agonists.

Beta-adrenergic blockers may weaken the effect of olodaterol or counteract this effect. Therefore, Olodaterol should be used together with beta-adrenergic blockers (including eye drops) only in forced situations. In this case, the use of cardioselective beta-blockers is preferable (with caution).

MAO inhibitors, tricyclic antidepressants, or other drugs that can prolong the QT_c interval may enhance the effect of olodaterol on the cardiovascular system.

Concomitant use of olodaterol with ketoconazole led to an increase in the bioavailability of olodaterol by 1.7 times, but this did not affect safety; dose adjustment is not required.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.